AR/ERK co-targeting triggers ferroptosis via FOXC2 in triple-negative breast cancer

Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, notably lacks effective treatment strategies. Although androgen receptor (AR) has emerged as a potential therapeutic target for TNBC, monotherapy with AR inhibitors has proven to be of restricted efficacy. Aiming to develop superior therapeutic approaches, a comprehensive drug library screening was conducted. The ERK inhibitor GDC-0994 exhibited significant synergistic effects with the AR inhibitor bicalutamide. Transcriptome sequencing showed that this combination therapy activates ferroptosis, as evidenced by elevated ROS, increased Fe2+ levels, a reduced GSH/GSSG ratio, and lipid peroxide accumulation (MDA and 4-HNE). FOXC2 was identified as a key mediator of this synergy. Specifically, the combination therapy inhibits FOXC2-driven EMT and induces ferroptosis via the FOXC2-Hippo signaling axis, suppressing tumor proliferation, migration, and invasion. In summary, this study uncovers the value of AR/ERK co-targeting in TNBC, which might potentiate the development of novel targeted therapeutic strategies in TNBC.